A cardinal feature of cancer cells is their unrestrained growth due to the excessive activation of signaling pathways that control cell proliferation and survival. It is firmly established that Ras proteins are essential control elements of growth promoting signaling networks. Moreover, the deregulation of Ras signaling has been causally linked to a number of human malignancies. However, our understanding of molecular principles that govern the physiologic and pathogenic activities of Ras proteins is still limited. The broad objective of this ongoing research program is to elucidate these principles and to determine how they are functionally linked to the control of cellular homeostasis. During the present funding period we have identified several components within the Ras regulatory circuitry whose function is to specify signaling outputs. Building on these identifications, the studies proposed in the current application are directed at gaining new insights into signaling platforms that mediate Ras-driven oncogenesis. We will exploit subcellular, cellular and organismal models to pursue the following aims: 1. To define the mechanisms of regulation and functional implications of Ras ubiquitination. Studies proposed within this aim will be directed at the identification of the molecular machinery that regulates Ras ubiquitination, and the elucidation of the contribution of ubiquitination to Ras oncogenicity. 2. To elucidate context-dependent mechanisms that link mutational activation of Ras to pancreatic cancer development. Studies proposed within this aim will explore the functional significance of the co-activation of Ras and the ErbB signaling axis for pancreatic neoplasia, and define the relevance of cross-talk mechanisms between Ras activation and the immune response. Together, these studies will enhance our knowledge of fundamental mechanisms by which Ras executes its oncogenic program and may uncover new modalities for therapeutic intervention.